Download - Synthesis of Valerenic Acid
Identifying Reaction Types
Total Synthesis of Valerenic Acid, a GABAA response modulator
For each step
• Assign class of transformation:
• Assign Conditions:
• Look for:
AdditionElimination
SubstitutionRearrangement
Polar BasicPolar AcidicRadical
PericyclicTransition Metal
Acidic SitesNucleophilic SitesElectrophilic Sites
Step 1: A Grignard Reaction
OH
MgBr
THFHO
OH
BrMg
-bond electrophile
-bond nucleophile
Step 2: Silyl Protection
HO
TBSClDIPEA
DCM TBSO
OSi Cl
-bond electrophile LP nucleophile
Step 3: Ene-Yne Metathesis
TBSOOTBS
Grubbs I
DCM
ethylene
22 oC
Step 4: Deprotection
OHOTBS
TBAF, THF
22 oC
Step 1’: Isopropenylation
O Li
Et2O, 0 oC
LiO
Step 2’: Acidic Workup
LiO CF3CO2H
H2O
OH
Lewis Acid Electrophile
Step 3’: Chiral Resolution
OH
OAcLipase PS
MTBE, rtOAc
+
OH
1 : 1
Step 4’: Recycling
OH OAc
SiO2, THF/H2O, rt
Step 5: Building the Ring System
OH
MgBr2*Et2ODIPEADCM, rt
O
O HO
O
Step 6: Reduction
HO
O
DIBALH
DCM
-78 oC HO
OH
Step 7: Wittig Reaction
HO
OH
Ph3P=CMeCO2EtPhH, reflux
HHO
CO2Et
HO
OH
hemiacetal
HHOO
Ph3P CCO2Et
Me
-bond nucleophile
Step 8: Hydrogenation
HHO
CO2Et
Crabtree's Cat.
H2, DCM, 22 oC
HHO
CO2Et
H
Step 9: Oxidation
HHO
CO2Et
H IBX, DMSO
22 oC
HO
CO2Et
H
Step 10: Making an Enol Triflate
HO
CO2Et
H Tf2O, pyridine
DCM, 22 oC
TfO
CO2Et
H
Step 11: Methylation
TfO
CO2Et
H Pd(PPh3)4, TF
0 oC, 15 min
then Me2Zn,
22 oC, 15 h
CO2Et
H
Step 12: Hydrolysis
CO2Et
H LiOH, H2O, THF
CH3OH, 22 oC
CO2H
H
Valerenic Acid